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Journal of Neuroimmunology Feb 2021Daclizumab (DAC), a humanized monoclonal antibody that binds to the interleukin (IL)-2-receptor alpha chain, was approved in May 2016 for treatment of...
Daclizumab (DAC), a humanized monoclonal antibody that binds to the interleukin (IL)-2-receptor alpha chain, was approved in May 2016 for treatment of relapsing-remitting multiple sclerosis (RRMS). Approval was suspended in March 2018 after occurrence of severe liver failure and fatal meningoencephalitis in several patients treated with DAC. We report the clinical, laboratory and neuroimaging findings of 2 patients, who developed hypophysitis about 4 months after cessation of therapy with DAC. This report identifies delayed onset hypophysitis as a previously unrecognized severe side effect of DAC, highlighting the importance of continuous pharmacovigilance and patient monitoring even after cessation of DAC therapy.
Topics: Daclizumab; Female; Humans; Hypophysitis; Immunosuppressive Agents; Middle Aged; Multiple Sclerosis, Relapsing-Remitting
PubMed: 33387829
DOI: 10.1016/j.jneuroim.2020.577469 -
Revista de Neurologia Apr 2018
Topics: Daclizumab; Humans; Immunosuppressive Agents; Interferon-beta; Multiple Sclerosis
PubMed: 29645067
DOI: No ID Found -
Transplantation Proceedings 2001
Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Drug Administration Schedule; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Middle Aged; Postoperative Complications; Prospective Studies; Tacrolimus
PubMed: 11267408
DOI: 10.1016/s0041-1345(00)02583-5 -
Clinical Transplantation 2002Tacrolimus inhibits lymphocyte responses by blocking calcium-dependent signalling pathways important in IL-2 generation. Daclizumab, a humanized monoclonal antibody,... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Tacrolimus inhibits lymphocyte responses by blocking calcium-dependent signalling pathways important in IL-2 generation. Daclizumab, a humanized monoclonal antibody, binds with high affinity to the Tac subunit of the IL-2 receptor complex. We reasoned therefore that the absence of IL-2R should permit lower doses of tacrolimus and thereby less toxicity. Twenty-eight patients were randomized and followed for 6 months: Group 1, high dose (HD) tacrolimus (trough 12-17 ng/mL; n = 13); Group 2, low dose (LD) tacrolimus (trough 5-10 ng/mL; n = 15). All patients received daclizumab induction (2 mg/kg) on days 0 and 14, mycophenolate mofetil (2 g/d except for one patient who received 1 g) and rapid prednisone taper. Serious infections were minimal in both groups. Hospitalizations, for various reasons, were HD (n = 12) and LD (n = 6). All patients and grafts survived for the 6-month study period. There was one rejection episode in a non-compliant patient at 101 d. LD tacrolimus appears equally effective as HD tacrolimus in preventing rejection episodes and may be associated with fewer adverse events.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; Male; Tacrolimus
PubMed: 12372041
DOI: 10.1034/j.1399-0012.16.s7.4.x -
American Journal of Ophthalmology Nov 2009To provide preliminary data regarding the safety and efficacy of high-dose intravenous daclizumab (Zenapax; Roche Inc, Nutley, New Jersey, USA) therapy for the treatment...
PURPOSE
To provide preliminary data regarding the safety and efficacy of high-dose intravenous daclizumab (Zenapax; Roche Inc, Nutley, New Jersey, USA) therapy for the treatment of juvenile idiopathic arthritis (JIA)-associated active anterior uveitis.
DESIGN
Interventional case series; open-label prospective, phase II pilot study.
METHODS
Six patients were recruited into the study and received daclizumab therapy at doses of 8 mg/kg at baseline, 4 mg/kg at week 2, and 2 mg/kg every 4 weeks thereafter, for a total of 52 weeks. The study was done at the National Eye Institute between June 29, 2005 and July 9, 2008. The primary outcome was a two-step decrease in inflammation grade assessed at week 12. Primary safety outcome was assessed at weeks 2 and 4. The ocular inflammation was assessed according to the Standardization of Uveitis Nomenclature criteria.
RESULTS
Four of the 6 participants achieved two-step reduction in anterior chamber cells according to Standardization of Uveitis Nomenclature Working Group grading scheme for anterior chamber cells 12 weeks into the study and met the primary efficacy endpoint. One additional patient responded to reinduction whereas 1 patient failed reinduction and was considered an ocular treatment failure. Visual acuity improved from a mean of 68 Early Treatment Diabetic Retinopathy Study letters in the worse eye to a mean of 79.6 letters (2 Snellen lines). Three participants were terminated before 52 weeks: First, because of a rash possibly induced by daclizumab; Second, because of ocular treatment failure; and Last, because of uncontrolled systemic manifestations of JIA.
CONCLUSION
High-dose intravenous daclizumab can help reduce active inflammation in active JIA-associated anterior uveitis; however, patients need to be monitored for potential side effects. Larger randomized trials are needed to better assess treatment effect and safety.
Topics: Adolescent; Anterior Chamber; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Juvenile; Child; Daclizumab; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Infusions, Intravenous; Male; Pilot Projects; Prospective Studies; Treatment Outcome; Uveitis, Anterior; Visual Acuity
PubMed: 19664754
DOI: 10.1016/j.ajo.2009.06.003 -
Cell Research Dec 2010Interleukin-2 (IL)-2 signaling plays a pivotal role in the activation of immune responses, and drugs that block this pathway have been shown to be effective for the...
Interleukin-2 (IL)-2 signaling plays a pivotal role in the activation of immune responses, and drugs that block this pathway have been shown to be effective for the immunosuppression in patients with organ transplantation to alleviate/eliminate allograft rejection. The first humanized monoclonal antibody (mAb) daclizumab falls into this category and shows high specificity and affinity against a key component of the IL-2 receptor complex, namely IL-2Rα. To reveal the molecular mechanism of the inhibition of the IL-2 signaling pathway by daclizumab, we determined the crystal structures of the daclizumab Fab in free form and in complex with the IL-2Rα ectodomain at 2.6 and 2.8 Å resolution, respectively. The daclizumab Fab adopts a similar conformation in the presence or absence of the IL-2Rα ectodomain. The antigen-binding site of daclizumab is mainly composed of five complementarity determining regions (CDRs) that form a large positively charged surface depression and two flanking patches that are generally hydrophobic. The conformational epitope consists of several discontinuous segments of the IL-2Rα ectodomain, a large portion of which overlaps with the regions that interact with IL-2, suggesting that the binding of daclizumab to IL-2Rα would prevent the IL-2 binding to IL-2Rα and the subsequent formation of the IL-2/IL-2Rαβγ(c) complex, and therefore block the IL-2 signaling pathway. These results also have implications for the design and development of improved mAb drugs targeting IL-2Rα.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Basiliximab; Binding Sites; Complementarity Determining Regions; Crystallography, X-Ray; Daclizumab; Graft Rejection; Humans; Hydrogen Bonding; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Protein Binding; Protein Structure, Tertiary; Recombinant Fusion Proteins; Signal Transduction
PubMed: 20820193
DOI: 10.1038/cr.2010.130 -
Multiple Sclerosis and Related Disorders Feb 2019Daclizumab, a MS treatment targeting IL2-receptor, has been recently withdrawn following reports of immune-mediated encephalitis. We report the case of a 39-years-old...
Daclizumab, a MS treatment targeting IL2-receptor, has been recently withdrawn following reports of immune-mediated encephalitis. We report the case of a 39-years-old woman treated with daclizumab that presented a progressive decrease in the strength at her lower limbs which further worsened after the drug was stopped. Post-treatment MRI showed more than 20 new enhancing lesions. No symptoms nor signs associated with immune-mediated encephalitis were present. Our case highlights the problem of disease course after daclizumab discontinuation and urge neurologists to strictly monitor patients discontinuing the drug in order to exclude both the occurrence of immune-mediated encephalitis and disease reactivation.
Topics: Adult; Brain; Daclizumab; Disease Progression; Drug Substitution; Female; Humans; Immunosuppressive Agents; Multiple Sclerosis; Safety-Based Drug Withdrawals
PubMed: 30554038
DOI: 10.1016/j.msard.2018.11.034 -
Transplant Immunology Mar 2005Stimulated human T cells from healthy volunteers demonstrate attenuated early interleukin (IL)-2 receptor (R) signaling in the presence of daclizumab (Dac). Aiming to...
Stimulated human T cells from healthy volunteers demonstrate attenuated early interleukin (IL)-2 receptor (R) signaling in the presence of daclizumab (Dac). Aiming to confirm that this ex-vivo effect of Dac is also observed in-vivo, we studied T cells from 3 kidney transplant recipients before and 2-3 weeks and 4-6 months after transplantation. We found by flow cytometry that T cells obtained pre-transplant and stimulated ex-vivo with phytohemeagglutinine upregulated the IL-2R alpha-(CD25) and beta-(CD122) chains as expected. Moreover, exogenous IL-2 induced characteristic tyrosine phosphorylation events detectable by immunoblotting in these cells. However, T cells studied post-transplant neither exhibited CD25 or -122 upregulation nor IL-2-induced tyrosine phosphorylation events, indicating broad, persistent suppression of the IL-2R signaling machinery which thus appears largely inaccessible for Dac in actual transplant recipients. We therefore conclude that the clinical efficacy of this agent may depend on additional mechanisms in-vivo other than those identified ex-vivo.
Topics: Adolescent; Age Factors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Down-Regulation; Humans; Immunoglobulin G; Kidney Transplantation; Receptors, Interleukin-2; Signal Transduction; T-Lymphocytes
PubMed: 15814281
DOI: 10.1016/j.trim.2004.12.001 -
Clinical Pharmacokinetics Oct 2014Daclizumab is a humanized monoclonal antibody that blocks the α-subunit of the interleukin-2 receptor with demonstrated benefits in the treatment of multiple sclerosis.... (Randomized Controlled Trial)
Randomized Controlled Trial
Population pharmacokinetics of daclizumab high-yield process in healthy volunteers: integrated analysis of intravenous and subcutaneous, single- and multiple-dose administration.
BACKGROUND AND OBJECTIVE
Daclizumab is a humanized monoclonal antibody that blocks the α-subunit of the interleukin-2 receptor with demonstrated benefits in the treatment of multiple sclerosis. The present work aimed to characterize the pharmacokinetics of daclizumab high-yield process (HYP) in healthy volunteers.
METHODS
Three double-blind, randomized, placebo-controlled, phase I studies evaluated the pharmacokinetics of daclizumab HYP in healthy volunteers following single subcutaneous administration (50, 150, or 300 mg), multiple subcutaneous administrations (100 or 200 mg biweekly with a 200 mg loading dose), or single intravenous administration (200 or 400 mg). Measurable serum concentrations (n = 925) from 70 subjects treated with daclizumab HYP in the three studies were analyzed using non-linear mixed-effects modeling.
RESULTS
A two-compartment model with a first-order absorption and elimination adequately described daclizumab HYP pharmacokinetics. Daclizumab HYP clearance, inter-compartmental clearance, and central and peripheral volumes of distribution were 10 mL/h, 44 mL/h, 3.89 L, and 2.52 L, respectively, scaled by [bodyweight (kg)/70] with 0.54 and 0.64 exponents for clearance and volume parameters, respectively. Lag-time, mean absorption time, and absolute bioavailability (100-300 mg) for subcutaneous administration were 2 h, 4.6 days, and 84 %, respectively. Bodyweight explained only ~20 % of daclizumab HYP pharmacokinetic variability. With this limited dataset, sex, age, race, or presence of antibodies did not correlate with daclizumab HYP clearance. The estimated effective half-life was 21-25 days. The developed model was robust in bootstrap evaluation and predicted the data adequately in stochastic simulations.
CONCLUSIONS
Daclizumab HYP is characterized by slow clearance, linear pharmacokinetics (at doses ≥100 mg), high subcutaneous bioavailability, and a half-life suitable for monthly administration.
Topics: Administration, Intravenous; Adolescent; Adult; Aged; Antibodies, Monoclonal, Humanized; Daclizumab; Double-Blind Method; Drug Administration Schedule; Female; Healthy Volunteers; Humans; Immunoglobulin G; Immunosuppressive Agents; Injections, Subcutaneous; Male; Middle Aged; Models, Biological; Protein Engineering; Young Adult
PubMed: 25212703
DOI: 10.1007/s40262-014-0159-9 -
The Lancet. Neurology Jan 2005
Review
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; CD4 Antigens; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Daclizumab; Humans; Immunoglobulin G; Immunosuppressive Agents; Multiple Sclerosis; Receptors, Interleukin-2; T-Lymphocytes
PubMed: 15620850
DOI: 10.1016/S1474-4422(04)00948-2